Selectivity of compounds isolated from the leaves of Nerium indicum Mill. on various human cancer cell lines.

The leaves of Nerium indicum Mill. have been utilized traditionally to cure cancer. By Bioassay (BST) guided isolation method, six compounds were isolated from the CHCl3 extract of the leaves. Selectivity of these compounds (in 0.6-12,500 ng/ml) was tested on various human cancer (MCF7, EVSA-T, T47D, H226, IGROV, A498, WIDR, M19, HeLa) and normal (Vero) cells in vitro. Doxorubicin and cysplatin were used as positive controls. The result indicated that NiO2D (5alpha-oleandrin) possessed the best cytotoxic effect on HeLa cells (IC50, 8.38 x10(-6) mM) and NiO2C (16, 17-dehidrodeasetil-5alpha-oleandrin) on A498 cells (IC50, 1.43 x 10(-6) mM). Those two compounds were not cytotoxic to normal cell.

Selectivity of compounds isolated from the leaves of Nerium indicum Mill. on various human cancer cell lines

The leaves of Nerium indicum Mill. have been utilized traditionally to cure cancer. By Bioassay (BST) guided isolation method, six compounds were isolated from the CHCl3 extract of the leaves. Selectivity of these compounds (in 0.6-12,500 ng/ml) was tested on various human cancer (MCF7, EVSA-T, T47D, H226, IGROV, A498, WIDR, M19, HeLa) and normal (Vero) cells in vitro. Doxorubicin and cysplatin were used as positive controls. The result indicated that NiO2D (5alpha-oleandrin) possessed the best cytotoxic effect on HeLa cells (IC50, 8.38 x10(-6) mM) and NiO2C (16, 17-dehidrodeasetil-5alpha-oleandrin) on A498 cells (IC50, 1.43 x 10(-6) mM). Those two compounds were not cytotoxic to normal cell.

A pharmacokinetic interaction study of docetaxel and cisplatin plus or minus 5-fluorouracil in the treatment of patients with recurrent or metastatic solid tumors.

BACKGROUND: The purpose of this study was to look at the pharmacokinetics of docetaxel, cisplatin-derived platinum and 5-fluorouracil (5-FU), when used in combination, to exclude potential clinically relevant pharmacokinetic interactions. METHODS: Fifteen patients with recurrent or metastatic solid tumors were randomized to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 in the first treatment course on day 1 and the same combination plus 5-FU 750 mg/m2/day on days 1-5 in the second course, or the two treatment courses in reversed order. Cycles were repeated every 3 weeks. A pharmacokinetic analysis was performed during the first two cycles. RESULTS: Full pharmacokinetic data was available for 12 of the 15 patients. Treatment was tolerated well, with frequency of toxicity consistent with the safety profile known for docetaxel, cisplatin and 5-FU. Mean clearance values for docetaxel and cisplatin showed no statistically significant difference across the "triple" and the "double" combination treatments, and the mean pharmacokinetic parameters of all agents were within the ranges for previously reported single agent treatment. CONCLUSION: No clinically relevant pharmacokinetic interactions between docetaxel, cisplatin and 5-FU used in combination were noticed in this study.

Lack of c-kit exon 11 activating mutations in c-KIT/CD117-positive SCLC tumour specimens.

Previous studies have shown that STI571, a selective tyrosine kinase inhibitor of c-KIT, is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumours (GIST), especially those that have activating mutations in the c-kit exon 11 that encodes the juxtamembrane (JM) domain of the c-KIT oncoprotein. We examined the prevalence of activating exon 11 c-kit mutations in 26 small-cell lung cancer (SCLC) cases in order to explore whether this disease is also a potential target for treatment with STI571. Expression of c-KIT, estimated by immunohistochemistry, was demonstrated in 14 out of 22 SCLC samples (64%); nine samples showed moderate to strong staining (41%), five samples were weakly positive (23%), whereas eight samples (36%) were negative for CD117. Next, we examined the mutational status of exon 11 of the c-kit gene, by single-stranded conformational polymorphism (SSCP) and sequencing in all of the cKIT/CD117-positive tumours. However, no activating mutations in the c-kit exon 11 were found by either technique. Apparently, c-KIT oncoprotein expression in SCLC was not correlated with activating mutations in c-kit exon 11. In analogy to GISTs, our results could imply that SCLC patients would not benefit from treatment with STI571.

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38.

We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC(500 h)) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC(500 h) using only two timed samples: AUC(500 h)=(6.588 x C(2.5 h))+(146.4 x C(49.5 h))+15.53, where C(2.5 h) and C(49.5 h) are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan.

Disposition of docetaxel in the presence of P-glycoprotein inhibition by intravenous administration of R101933.

Recently, a study of docetaxel in combination with the new orally administered P-glycoprotein (P-gp) inhibitor R101933 showed that this combination was feasible. However, due to the low oral bioavailability of R101933 and high interpatient variability, no further attempts to increase the level of P-gp inhibition were made. Here, we assessed the feasibility of combining docetaxel with intravenously (i.v.) administered R101933, and determined the disposition of docetaxel with and without the P-gp inhibitor. Patients received i.v. R101933 alone at a dose escalated from 250 to 500 mg on day 1 (cycle 0), docetaxel 100 mg/m(2) as a 1-h infusion on day 8 (cycle 1) and the combination every 3 weeks thereafter (cycle 2 and further cycles). 12 patients were entered into the study, of whom 9 received the combination treatment. Single treatment with i.v. R101933 was associated with minimal toxicity consisting of temporary drowsiness and somnolence. Dose-limiting toxicity consisting of neutropenic fever was seen in cycles 1 and 2 or in further cycles at both dose levels. The plasma pharmacokinetics of docetaxel were not changed by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 22.5+/-6.2 l/h/m(2) and 24.2+/-7.4 l/h/m(2) (P=0.38) in cycles 1 and 2, respectively. However, the faecal excretion of unchanged docetaxel decreased significantly after the combination treatment from 2.5+/-2.1% to less than 1% of the administered dose of docetaxel, most likely due to inhibition of the intestinal P-gp by R101933. Plasma concentrations of R101933 were not different in cycles 0 or 2 and the concentrations achieved in the first 12-h period after i.v. infusion were capable of inhibiting P-gp in an ex vivo assay. We conclude that the combination of 100 mg/m(2) i.v. docetaxel and 500 mg i.v. R101933 is feasible, lacks pharmacokinetic interaction in plasma, and shows evidence of P-gp inhibition both in an ex vivo assay and in vivo as indicated by the inhibition of intestinal P-gp.

Modulation of cisplatin pharmacodynamics by Cremophor EL: experimental and clinical studies.

The paclitaxel vehicle Cremophor EL (CrEL) has been shown to selectively inhibit the accumulation of cisplatin in peripheral blood leucocytes, but not in tumour cells in vitro, and we hypothesised that this phenomenon is responsible for the improvement of the therapeutic index of cisplatin observed in combination studies with paclitaxel. Here, we report on studies assessing the interaction between CrEL and cisplatin in a murine model, and involving the potential clinical applicability of CrEL as a protector for cisplatin-associated haematological side-effects. In mice, CrEL (0.17 ml/kg, intravenous (i.v.)) given in combination with cisplatin (10 mg/kg, intraperitoneal (i.p.)) did not change the pharmacokinetics of cisplatin. Cisplatin-induced haematological toxicity, expressed as white blood cells (WBC) at nadir, was significantly reduced by CrEL from 5.05+/-0.95 to 6.50+/-1.31 x 10(9)/l (P=0.0009). Data obtained from cancer patients treated with cisplatin (70 mg/m(2), 3-h i.v.) and topotecan (0.45 or 0.60 mg/m(2)/day x 2) preceded by CrEL (12 ml, 3-h i.v.) (n=6) or without CrEL (n=10) similarly indicated significant differences in the percent decrease in WBC between the groups (46.5+/-18.7 versus 67.2+/-15.0%; P=0.029). Likewise, the percent decrease in platelet count was significantly greater in the absence of CrEL (23.9+/-5.38 versus 73.3+/-15.5%; P=0.0003). Pharmacokinetic parameters of unbound and total cisplatin and of topotecan lactone and total drug were not significantly different from historic control values (P>or=0.245). Overall, this study provides further evidence on the important role of CrEL in the pharmacological and toxicological profile of cisplatin, and implies that reformulation of cisplatin with CrEL for systemic treatment might achieve an improvement of its therapeutic index, particularly in the setting of a weekly dose-dense concept.

The (ir)relevance of plasma protein binding of anticancer drugs.

The major purpose of therapeutic drug monitoring is to enable drug dosage individualization for differences among patients in rates of drug metabolism and/or excretion. The standard analytical methods for measuring concentrations of drugs in plasma determine drug bound to plasma proteins as well as free drug dissolved in plasma water. For this reason, the relationship between total drug concentration in plasma and treatment outcome (i.e. toxicity and efficacy) will only be good if the degree of plasma protein binding of the agent is constant, or if so little drug is protein bound that changes in binding make insignificant changes in unbound concentration. A review of available literature data indicates that, in general, protein binding of anticancer drugs is not of principal clinical relevance. However, there are several instances, in which monitoring of unbound concentrations might be useful: (i) agents demonstrating protein-concentration-dependent binding, (ii) agents that bind irreversible or near covalently, (iii) when formulation excipients modulate unbound drug levels, and (iv) metabolically interconvertible agents. While available evidence suggests that for these agents unbound drug levels correlate better with clinical effects than total plasma concentrations, there are insufficient data to justify the recommendation of the routine use of unbound drug concentration monitoring for any of these agents at present.

SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line.

The therapeutic potential of cisplatin, one of the most active and widely used anticancer drugs, is severely limited by the occurrence of cellular resistance. In this study, using budding yeast Saccharomyces cerevisiae as a model organism to identify novel drug resistance genes, we found that disruption of the yeast gene SKY1 (serine/arginine-rich protein-specific kinase from budding yeast) by either transposon insertion or one-step gene replacement conferred cellular resistance to cisplatin. Heterologous expression of the human SKY1 homologue SRPK1 (serine/arginine-rich protein-specific kinase) in SKY1 deletion mutant yeast cells restored cisplatin sensitivity, suggesting that SRPK1 is a cisplatin sensitivity gene, the inactivation of which could lead to cisplatin resistance. Subsequently, we investigated the role of SRPK1 in cisplatin sensitivity and resistance in human ovarian carcinoma A2780 cells using antisense oligodeoxynucleotides. Treatment of A2780 cells with antisense oligodeoxynucleotides directed against the translation initiation site of SRPK1 led to down-regulation of SRPK1 protein and conferred a 4-fold resistance to cisplatin. The human SRPK1 gene has not been associated with drug resistance before. Our new findings strongly suggest that SRPK1 is involved in cisplatin-induced cell kill and indicate that SRPK1 might potentially be of importance for studying clinical drug resistance.

Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure.

PURPOSE: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population. PATIENTS AND METHODS: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m(2) (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non-protein-bound cisplatin in plasma by atomic absorption spectrometry. RESULTS: No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CL(free)) was 57.1 +/- 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m(2) (mean, 1.86 +/- 0.19 m(2)), with an interpatient variability of 10.4%. When CL(free) was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CL(free) and BSA (r = 0.42). Intrapatient variability in CL(free), calculated from 90 patients was 12.1% +/- 7.8% (range, 0.30% to 32.7%). CONCLUSION: In view of the high interpatient variability in CL(free) relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.

Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation.

Cremophor EL (CrEL) is a formulation vehicle used for various poorly-water soluble drugs, including the anticancer agent paclitaxel (Taxol). In contrast to earlier reports, CrEL is not an inert vehicle, but exerts a range of biological effects, some of which have important clinical implications. Its use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidaemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy. The pharmacokinetic behaviour of CrEL is dose-independent, although its clearance is highly influenced by duration of the infusion. This is particularly important since CrEL can affect the disposition of various drugs by changing the unbound drug concentration through micellar encapsulation. In addition, it has been shown that CrEL, as an integral component of paclitaxel chemotherapy, modifies the toxicity profile of certain anticancer agents given concomitantly, by mechanisms other than kinetic interference. A clear understanding of the biological and pharmacological role of CrEL is essential to help oncologists avoid side-effects associated with the use of paclitaxel or other agents using this vehicle. With the present development of various new anticancer agents, it is recommended that alternative formulation approaches should be pursued to allow a better control of the toxicity of the treatment and the pharmacological interactions related to the use of CrEL.

Clinical pharmacokinetics and metabolism of irinotecan (CPT-11).

CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as a prodrug of SN-38, which is approximately 100-1000-fold more cytotoxic than the parent drug. CPT-11 has shown a broad spectrum of antitumor activity in preclinical models as well as clinically, with responses observed in various disease types including colorectal, lung, cervical, and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are extremely complex and have been the subject of intensive investigation in recent years. Both CPT-11 and SN-38 are known in an active lactone form and an inactive carboxylate form, between which an equilibrium exists that depends on the pH and the presence of binding proteins. CPT-11 is subject to extensive metabolic conversion by various enzyme systems, including esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as well as CYP3A4, which forms several pharmacologically inactive oxidation products. Elimination routes of CPT-11 also depend on the presence of drug-transporting proteins, notably P-glycoprotein and canalicular multispecific organic anion transporter, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. Strategies to individualize CPT-11 administration schedules based on patient differences in enzyme or protein expression or by coadministration of specific agents modulating side effects are under way and may ultimately lead to more selective chemotherapeutic use of this agent.

Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles.

Nonlinear disposition of paclitaxel (Taxol) in cancer patients has been described in several studies, but the underlying mechanism is still a matter of speculation. Previously, we have shown in vitro that the paclitaxel formulation vehicle, Cremophor EL (CrEL), alters the blood distribution of paclitaxel as a result of entrapment of the compound in circulating CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. Based on these findings, we prospectively re-evaluated the linearity of paclitaxel disposition in patients using whole blood and plasma analysis, and sought to define a new pharmacokinetic model to describe the data. Seven patients with solid tumors were treated with paclitaxel infused over 3 h, each at consecutive 3-weekly dose levels of 225, 175 and 135 mg/m2 (CrEL dose level, 18.8, 14.6, and 11.3 ml/m2, respectively). Patient samples were collected up to 24 h after the start of infusion, and analyzed by high-performance liquid chromatography. Paclitaxel peak levels and areas under the curve in whole blood increased linearly with dose, whereas plasma levels showed substantial deviation from linearity. This was shown to be caused by a CrEL concentration-dependent decrease in paclitaxel uptake in blood cells, as reflected by the blood:plasma concentration ratios which altered significantly from 0.83 +/- 0.11 (at 135 mg/m2) to 0.68 +/- 0.07 (at 225 mg/m2). It is concluded that the nonlinear disposition of paclitaxel is related to paclitaxel dose-related levels of the formulation vehicle CrEL, leading to a disproportionate drug accumulation in the plasma fraction. The pharmacokinetic model developed accurately described the data, and will help guide future development and refinement of clinical protocols, especially in defining the exposure measure best linked to paclitaxel effects and toxicities.

Development of multidrug-resistance convertors: sense or nonsense?

This review describes the clinical relevance of the two drug transporters P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) and the in vitro phenomenon which is referred to as multidrug resistance (MDR). The attempts to try to block these resistance mechanisms are summarized with specific attention for the intentionally designed "second generation" MDR-convertors. Potential explanations of the limited clinical success rate are given and recommendations for the design of future studies provided.

Role of intestinal P-glycoprotein in the plasma and fecal disposition of docetaxel in humans.

Multidrug resistance (MDR)-1-P-glycoprotein (P-gp) is a drug-transporting protein that is abundantly present in biliary ductal cells and epithelial cells lining the gastrointestinal tract. Here, we have determined the role of P-gp in the metabolic disposition of the antineoplastic agent docetaxel (Taxotere) in humans. Pharmacokinetic profiles were evaluated in five cancer patients receiving treatment cycles with docetaxel alone (100 mg/m2 i.v. over a 1-h period) and in combination with a new potent inhibitor of P-gp activity, R101933 (200-300 mg b.i.d.). The terminal disposition half-life and total plasma clearance of docetaxel were not altered by treatment with oral R101933 (P > or = 0.27). The cumulative fecal excretion of docetaxel, however, was markedly reduced from 8.47 +/- 2.14% (mean +/- SD) of the dose with the single agent to less than 0.5% in the presence of R101933 (P = 0.0016). Levels of the major cytochrome P450 3A4-mediated metabolites of docetaxel in feces were significantly increased after combination treatment with R101933 (P = 0.010), indicating very prominent and efficient detoxification of reabsorbed docetaxel into hydroxylated compounds before reaching the systemic circulation. It is concluded that intestinal P-gp plays a principal role in the fecal elimination of docetaxel by modulating reabsorption of the drug after hepatobiliary secretion. In addition, the results indicate that inhibition of P-gp activity in normal tissues by effective modulators, and the physiological and pharmacological consequences of this treatment, cannot be predicted based on plasma drug monitoring alone.

Liposomal lurtotecan (NX211): determination of total drug levels in human plasma and urine by reversed-phase high-performance liquid chromatography.

Lurtotecan (GI147211; LRT) is a semisynthetic and water-soluble analogue of the topoisomerase I inhibitor camptothecin. To determine whether the therapeutic efficacy of LRT in patients could be improved, the drug was encapsulated in liposomes (NX211; Gilead Sciences). In order to allow accurate description of the pharmacokinetic behavior of NX211 in cancer patients, we have developed sensitive RP-HPLC assays with fluorescence detection (lambdaex=378 nm; lambdaem=420 nm) for the determination of total LRT levels in human plasma and urine. Sample pretreatment involved deproteinization with 10% (w/v) aqueous perchloric acid-acetonitrile (2:1, v/v), and chromatographic separations were achieved on an Inertsil-ODS 80A analytical column. The lower limit of quantitation (LLQ) was established at 1.00 ng/ml in plasma (200-microl sample) and at 100 ng/ml in urine (200 microl of 40-fold diluted sample). The within-run and between-run precisions were <7.5%. LRT concentrations in urine of <100 ng/ml were determined by a modified procedure comprising a single solvent extraction with n-butanol-diethyl ether (3:4, v/v). In this assay, the fluorescence signal of LRT was increased 14-fold prior to detection by post-column exposure to UV light (254 nm) in a photochemical reaction unit. The LLQ of this assay was 0.500 ng/ml (150-microl sample) and the within-run and between-run precisions were <10%.

A genome-wide screening in Saccharomyces cerevisiae for genes that confer resistance to the anticancer agent cisplatin.

Cisplatin is a potent DNA-damaging agent that has demonstrated anticancer activities against several tumors. However, manifestation of cellular resistance is a major obstacle in anticancer therapy that severely limits the curative potential of cisplatin. Therefore, understanding the molecular basis of cisplatin resistance could significantly improve the clinical efficacy of this anticancer agent. Here, we employed Saccharomyces cerevisiae as a model organism to study cisplatin resistance mechanisms and describe a one-step cisplatin selection to identify and characterize novel cisplatin resistance genes. Screening a multicopy yeast genomic library enabled us to isolate several yeast clones for which we could confirm that the cisplatin resistance phenotype was linked to the introduced fragment. In a first attempt, a number of open reading frames could be identified. Among these genes, PDE2 and ZDS2 were repeatedly identified as genes whose overexpression confers cellular resistance to cisplatin. PDE2, encoding cAMP-phosphodiesterase 2, is of particular interest because the overexpression of this yeast gene is known to induce cisplatin resistance in mammalian cells as well, providing proof of the principle of our experimental approach. In addition, the identification of PDE2 shows that our yeast screening system can directly be informative for drug resistance in mammalian cells.

Clinical pharmacokinetics of doxorubicin in combination with GF120918, a potent inhibitor of MDR1 P-glycoprotein.

Previous clinical investigations with doxorubicin indicated that modulators of P-glycoprotein dramatically decrease the systemic clearance of the drug, which complicates the interpretation of toxicity and response data. In the present study, we examined the pharmacokinetics of doxorubicin and GF120918, a novel potent P-glycoprotein inhibitor, in cancer patients in a search for more selective modulation of multidrug resistance (MDR). Seven cohorts (46 patients) received sequential treatments with doxorubicin alone by a 5 min i.v. bolus (50-75 mg/m2), oral GF120918 alone (50 mg q.d.-400 mg b.i.d.), and the combination of doxorubicin and GF120918. Serial blood and urine samples were taken during both treatment courses and analyzed for doxorubicin and its metabolite doxorubicinol by a liquid chromatographic assay. The pharmacokinetic characteristics of doxorubicin in the presence or absence of GF120918 indicate a very minor overall effect of the modulator, except at the highest combined dose level (i.e. 75 mg/m2 plus 400 mg b.i.d.). A limited number of patients experienced significantly increased exposure to doxorubicinol upon combined treatment, which was associated with concomitantly higher plasma levels of GF120918. Sigmoidal maximum-effect models revealed significant correlations (p<0.02) between the area under the curve of doxorubicinol and the percent decrease in neutrophils and platelets. Sigmoidicity factors in the fitted Hill equation were similar between both treatment courses, suggesting no pharmacodynamic potentiation of doxorubicinol myelotoxicity by GF120918. Our data indicate that GF120918 at the tested doses of combination treatment achieves plasma concentrations that reverse MDR in experimental models and it lacks the significant kinetic interaction with doxorubicin observed previously with other modulators. Hence, it may be possible in future trials to assess the contribution of a potent inhibitor of P-glycoprotein activity to the toxicity and activity of doxorubicin with the knowledge that profound plasma pharmacokinetic interactions are unlikely.

Disposition of [G-(3)H]paclitaxel and cremophor EL in a patient with severely impaired renal function.

In the present work, we studied the pharmacokinetics and metabolic disposition of [G-(3)H]paclitaxel in a female patient with recurrent ovarian cancer and severe renal impairment (creatinine clearance: approximately 20 ml/min) due to chronic hypertension and prior cisplatin treatment. During six 3-weekly courses of paclitaxel at a dose level of 157.5 mg/m(2) (viz. a 10% dose reduction), the renal function remained stable. Pharmacokinetic evaluation revealed a reproducible and surprisingly high paclitaxel area under the plasma concentration-time curve of 26.0 +/- 1.11 microM.h (mean +/- S.D.; n = 6; c.v. = 4.29%), and a terminal disposition half-life of approximately 29 h. Both parameters are substantially increased ( approximately 1.5-fold) when compared with kinetic data obtained from patients with normal renal function. The cumulative urinary excretion of the parent drug was consistently low and averaged 1.58 +/- 0.417% (+/- S.D.) of the dose. Total fecal excretion (measured in one course) was 52.9% of the delivered radioactivity, and mainly comprised known mono- and dihydroxylated metabolites, with unchanged paclitaxel accounting for only 6.18%. The plasma area under the plasma concentration-time curve of the paclitaxel vehicle Cremophor EL, which can profoundly alter the kinetics of paclitaxel, was 114.9 +/- 5.39 microl.h/ml, and not different from historic data in patients with normal or mild renal dysfunction. Urinary excretion of Cremophor EL was less than 0.1% of the total amount administered. These data indicate that the substantial increase in systemic exposure of the patient to paclitaxel relates to decreased renal metabolism and/or urinary elimination of polar radioactive species, most likely lacking an intact taxane ring fragment.

Prediction of the systemic exposure to oral 9-amino-20(S)-camptothecin using single-sample analysis.

The purpose of this study was to develop and validate limited-sampling strategies for prediction of the area under the plasma-concentration time curves (AUCs) of the lactone and total (i. e., lactone plus carboxylate) forms of the novel topoisomerase-I inhibitor 9-amino-20(S)-camptothecin (9-AC). Complete pharmacokinetic curves for both drug species were obtained from 32 patients who received the drug orally in a clinical phase I setting at dose levels ranging from 0.25 to 1.10 mg/m2. The concentrations of the lactone and carboxylate forms of 9-AC in plasma were measured by HPLC. Using data from 20 randomly selected patients, forward-stepwise multivariate regression analysis was used to generate modeling strategies incorporating data from one, two, or three plasma samples. The simultaneous optimal prediction of both 9-AC lactone and 9-AC total AUCs was obtained with sample time points at 0.33, 3.0, and 11.0 h after drug dosing. Validation of the models on an independent data set comprising data of the remaining 12 patients demonstrated that 9-AC lactone and 9-AC total AUCs could be predicted sufficiently unbiased and precise using one and two time points: [AUC (ng. h/ml) = 7.103*C3 + 4.333] for 9-AC lactone and [AUC (ng. h/ml) = 9.612*C3 + 13.77*C11 - 44.11] for 9-AC total, where C3 and C11 represent the 9-AC plasma concentrations in ng/ml at 3 and 11 h after drug dosing. Application of the proposed models will be valuable in the determination of 9-AC population pharmacokinetics and permits treatment optimization for patients on the basis of individual pharmacokinetic characteristics through restricted drug monitoring in clinical routines.